Dr. Remi Creusot's Research

Dr. Remi Creusot’s Research

Immune tolerance and autoimmunity: a brief introduction

Immune tolerance is a process by which the body eliminates or suppresses T cells that may react against self or innocuous environmental antigens. Defects in immune tolerance can lead to autoimmune or allergic disorders. In the case of Type 1 diabetes (T1D) for example, T cells reactive to pancreatic beta-cell antigens are not properly eliminated and/or controlled. The role of eliminating or educating self-reactive T cells is normally fulfilled by specialized “tolerogenic” cells that interact with immune cells, primarily within the thymus, the lymph nodes and the spleen. These cells are referred to as tolerogenic because of two important properties: (1) the ability to present self-antigens (either expressed endogenously or acquired from their surrounding environment) and, as a consequence, to form antigen-specific contacts with self-reactive T cells, and (2) the ability to deliver tolerogenic signals that will cause the deletion or inhibition of those self-reactive T cells, or the induction of suppressive – rather than destructive – functions within those self-reactive T cells. During their development in the thymus, self-reactive T cells have an opportunity to recognize their self-antigens on tolerogenic cells and be adequately dealt with before they can be released into the circulation. Thus, many potentially self-reactive T cells, while in the thymus, can be eliminated or converted into regulatory T cells, which block other self-reactive T cells and protect our tissues from autoimmunity. This process is not perfect, even in healthy individual: some self-reactive T cells escape this selection process and get a step closer to reacting against self-tissues. Fortunately, there are additional tolerogenic cells that T cells can later encounter while circulating in the body, and which constitute one of the focuses of the lab.

Tolerogenic antigen-presenting cells comprise two types of cells:
1) Dendritic cells: they can exogenously acquire self-antigens in tissues and transport them to lymphoid tissues for presentation. They exist under two functional modes: tolerogenic or immunogenic. While their immunogenic mode is useful to fight infections and tumors, it is their tolerogenic mode that we aim to understand and exploit.
2) Stromal cells: these are non-professional antigen-presenting cells that are incapable of mounting immune responses, but have the ability to suppress some autoimmune responses.

Particular stromal cells in the thymus have the ability to express tissue-specific antigens, which is conferred by the function of the protein AIRE. The importance of this process is demonstrated by the observation that AIRE-deficiency in both humans and mice leads to a severe autoimmune syndrome targeting multiple tissues (T1D is observed in ~20% of cases). We have recently discovered that endogenous expression of tissue-specific antigens can also be regulated by DEAF1, a regulator of gene expression that has homologies with AIRE. In both T1D patients and NOD mouse model of T1D, the progression of disease is associated with a defective function of DEAF1 due the alternative mRNA splicing in the pancreatic lymph nodes. In the case of T1D, pancreatic lymph nodes are central, both a major site of disease initiation and a site of competition between tolerogenic and immunogenic cells that present beta-cell antigens. Thus inability of tolerogenic cells to express tissue-specific antigens in this tissue may tip the balance in favor of immunogenic cells eliciting diabetogenic responses.

Research Interests

Ø Although DEAF1 is widely expressed as opposed to AIRE, it has unique functions that are dependent on the cell types in which it is expressed. We are particularly interested in studying the role and function of DEAF1 in tolerogenic cells, and the relevance of its association with T1D. Both the NOD mouse model of T1D and human lymphoid tissues are used in our studies.

Ø Distinct populations of tolerogenic cells, stromal or dendritic, are unique in the tolerogenic molecules and pathways that they utilize to mediate immune tolerance, resulting in different outcomes. We study ways to create more powerful tolerogenic cells that can be used to treat T1D by reprograming harmful T cells into protective T cells.